Pixatimod (PG545) Plus Nivolumab in PD-1 Relapsed/Refractory Metastatic Melanoma and NSCLC and With Nivolumab and Low-dose Cyclophosphamide in MSS Metastatic Colorectal Carcinoma (mCRC)

  • STATUS
    Recruiting
  • End date
    Sep 27, 2026
  • participants needed
    61
  • sponsor
    Diwakar Davar
Updated on 27 April 2022
measurable disease
carcinoma
squamous cell carcinoma
BRAF
KRAS
progressive disease
pembrolizumab
EGFR
nivolumab
targeted therapy
lung carcinoma

Summary

The primary goal of this trial is to assess clinical response to nivolumab and pixatimod, and, nivolumab, pixatimod and cyclophosphamide in three separate patient cohorts. Cohort 1: MSS mCRC in combination with low-dose cyclophosphamide, Cohort 2: PD-1 relapsed/refractory melanoma, and Cohort 3: PD-1 relapsed/refractory NSCLC.

Description

Nivolumab is approved by the FDA for the treatment of melanoma, non-small cell lung cancer (NSCLC), malignant pleural mesothelioma, renal cell carcinoma, classical Hodgkin lymphoma, squamous cell carcinoma of head/neck, urothelial carcinoma, MSI-H colorectal cancer, hepatocellular carcinoma, gastric carcinoma and gastroesophageal junction (GEJ) cancer.

Pixatimod is an investigational drug that activates the toll-like receptor 9 (TLR9) pathway and is being evaluated in studies involving melanoma, non-small cell lung cancer, and microsatellite stable colorectal cancer.

Cyclophosphamide is approved by the FDA for the treatment of acute lymphoblastic leukemia, acute monocytic leukemia, acute myeloid leukemia, breast cancer, chronic granulocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin lymphoma, multiple myeloma, mycosis fungoides, neuroblastoma, non-Hodgkin lymphoma, ovarian cancer, retinoblastoma. Low-dose (immunomodulatory) cyclophosphamide is being studied in combination with various types of immunotherapy including nivolumab and pembrolizumab.

This Phase llA trial hypothesizes that the nivolumab/pixatimod combination in PD-1 relapsed/refractory (R/R) cutaneous melanoma and NSCLC patients will be associated with anti-tumor effects, and that the nivolumab/pixatimod/cyclophosphamide combination in MSS mCRC patients will be associated with anti-tumor effect.

In the 1st stage, 13 patients will be enrolled in cohort 1 while 9 patients each will be enrolled in cohorts 2 and 3. Should the pre-specified efficacy boundary met, further patients will be enrolled to one or more cohorts in 2nd stage. The total enrollment for 1st stage across all 3 cohorts is 31 response-evaluable patients. The total enrollment for both stages across all 3 cohorts is 61 response-evaluable patients.

Details
Condition NSCLC, Metastatic Colorectal Carcinoma, Refractory Melanoma
Treatment Nivolumab, Pixatimod, Cyclophosphamide (low dose)
Clinical Study IdentifierNCT05061017
SponsorDiwakar Davar
Last Modified on27 April 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

General Inclusion Criteria
Male/female participants who are at least 18 years of age on the day of signing informed consent with advanced/metastatic cutaneous melanoma, NSCLC or MSS mCRC who meet the following criteria will be enrolled in this study
Male participants
A male participant must agree to use a contraception during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period
Female participants
A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies
Not a woman of childbearing potential (WOCBP);OR
A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment
Cohort 1 (MSS mCRC)
MSS is defined as 0-1 allelic shifts among 3-5 tumor microsatellite loci using a PCR-based assay or immunohistochemistry
Must have received prior therapy with a fluoropyrimidine, oxaliplatin, and irinotecan
Prior treatment with an anti-PD-1/anti-PD-L1 or anti-CTLA-4 antibody is not allowed
Prior treatment with BRAF/MEK inhibitor therapy (if BRAF mutated) and/or EGFR targeted antibody (if KRAS WT) are allowed
No more than 2 prior lines of therapy for metastatic disease
Adjuvant therapy will count as 1 prior line of therapy if received within the prior 6 months; but if not does not count towards prior line of therapy
Cohort 2 (PD-1 R/R melanoma)
PIV (pan-immune-inflammation) cutoff of 1200 obtained on labs obtained during Screening
PD-1 refractory disease as defined as progression on treatment with anti-PD-(L)1 inhibitor administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the following criteria
Receipt of at least 2 doses of an approved or investigational anti-PD-(L)1 inhibitor
Demonstrated PD after anti-PD-(L)1 inhibitor as defined by RECIST v1.1. The initial evidence of PD is to be confirmed by a second assessment no less than 4 weeks from the date of the first documented PD, in the absence of rapid clinical progression (as defined by the criteria in the sub-point below)
Progressive disease that has been documented within 12 weeks from the last dose of anti-PD-(L)1 inhibitor
Progressive disease is determined according to iRECIST
This determination is made by the investigator. Once PD is confirmed, the initial date of PD documentation will be considered the date of disease progression
Subjects who progressed on/within 3 months of adjuvant therapy with anti-PD-(L)1 inhibitor will be allowed; an adjuvant therapy will count as 1 prior line of therapy if received within the prior 6 months
Prior treatment with an anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody is allowed but not required
No more than 5 prior lines of therapy
Prior treatment with BRAF/MEK inhibitor therapy (if BRAF mutated) is allowed but not required
Cohort 3 (PD-1 R/R NSCLC)
PD-1 refractory disease as defined as progression on treatment with anti-PD-(L)1 inhibitor administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the following criteria
Has received at least 2 doses of an approved or investigational anti-PD-(L)1 inhibitor
Has demonstrated PD after anti-PD-(L)1 inhibitor as defined by RECIST v1.1. The initial evidence of PD is to be confirmed by a second assessment no less than 4 weeks from the date of the first documented PD, in the absence of rapid clinical progression (as defined by the criteria in the sub-point below)
Progressive disease has been documented within 12 weeks from the last dose of anti-PD-(L)1 inhibitor
Progressive disease is determined according to iRECIST
This determination is made by the investigator. Once PD is confirmed, the initial date of PD documentation will be considered the date of disease progression
Subjects who progressed on/within 3 months of adjuvant therapy with anti-PD-(L)1 inhibitor will be allowed; an adjuvant therapy will count as 1 prior line of therapy if received within the prior 6 months
Prior treatment with an anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody is allowed but not required
Patients with NSCLC with known oncogenic driver (including but not limited to EGFR, ALK, ROS, MET alterations) must have received and progressed past driver-specific therapy
Prior treatment with BRAF/MEK inhibitor therapy (if BRAF mutated) must have received and progressed or have demonstrable intolerance to approved targeted therapy
No more than 5 prior lines of therapy
Other Criteria
The participant (or legally acceptable representative if applicable) provides written informed consent for the trial
Have measurable disease based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
Have provided newly obtained core or excisional biopsy of a tumor lesion not previously irradiated to undergo tumor biopsy (core, punch, incisional or excisional)
Biopsy must meet minimal sampling criteria
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
Adequate organ function. Screening labs obtained within 4 weeks of Cycle 1 day 1
Evaluation of ECOG is to be performed within 28 days prior to the date of
Proteinuria exceeding 1gram in a 24 hour period
enrollment
Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
A pan-immune-inflammation (PIV) cutoff of 1200 (obtained on labs during Screening)
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject

Exclusion Criteria

Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment
History of allergy and/or hypersensitivity and/or other clinically significant adverse drug reaction to heparin or other anti-coagulant agents, or to any monoclonal antibody
Use of heparin (including low-molecular weight heparin and/or fondaparinux) within 2 weeks prior to enrollment
Patients who are currently receiving low-molecular weight heparin (or fondaparinux or other heparin product) for therapeutic anticoagulation may be enrolled if they have tested negative for anti-heparin antibodies at Screening
Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
Has a diagnosis of immunodeficiency, immunosuppression and/or is receiving systemic
steroid therapy or any other form of immunosuppressive therapy within 7 days
Active (i.e., symptomatic or growing) central nervous system (CNS) metastases
prior to the first dose of trial treatment
Note: Subjects with treated and stable CNS metastases are permitted to enroll. Stability for prior treated CNS disease should be assessed on a contrast-enhanced imaging study obtained no sooner than 14 days from data of definitive radiotherapy and/or surgery for CNS disease
Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent
Note: Subjects with leptomeningeal carcinomatosis are excluded
Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study
Has a systemic disease that requires systemic pharmacologic doses of corticosteroids greater than 10 mg daily prednisone (or equivalent)
Note: Subjects with autoimmune disorders of Grade 4 while on prior immunotherapy will be excluded. Subjects who developed autoimmune disorders of Grade ≤ 3 may enroll if the disorder has resolved to Grade ≤1 and the subject has been off systemic steroids at doses >10 mg/d for at least 2 weeks
Note: Subjects that require topical, ophthalmologic and inhalational steroids are not excluded from the study
Note: Subjects with hypothyroidism stable on hormone replacement or Sjogren's syndrome are not excluded from the study
Note: Subjects who require active immunosuppression (greater than steroid dose discussed above) for any reason are excluded from the study
Has a known additional malignancy that is progressing or requires active treatment
Has evidence of interstitial lung disease or active, non-infectious pneumonitis
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma
Has an active infection requiring systemic therapy
of the skin, or in situ cervical cancer that has undergone (or is being
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
planned to undergo) potentially curative therapy
Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 26 weeks after the last dose of trial treatment
Note: Subjects who are currently receiving steroids at a dose of ≤10 mg daily do not need to discontinue steroids prior to enrollment
Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
Note: Subjects with HIV that is well controlled (undetectable viral load and CD4 count >200 cells/mm3) on anti-retroviral therapy are permitted to enroll
Note: Subjects with treated hepatitis B and/or C with no evidence of active infection may be enrolled
Receipt of live vaccine(s) within 30 days prior to the first dose of trial treatment
Other uncontrolled intercurrent illness, including but not limited to, ongoing/active infection, active interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring adverse events and/or compromise the ability of the patient to give written informed consent
Has known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA
[qualitative] is detected
Has a history of significant cardiac disease including but not limited to symptomatic
congestive heart failure (New York Heart Association Class III/IV)
uncontrolled hypertension (≥150/90mmHg) despite appropriate anti-hypertensive
medication (patients with stably controlled hypertension are eligible)
unstable angina pectoris or myocardial infarction (≤ 6 months prior to
screening), uncontrolled cardiac arrhythmia, clinically significant cardiac
valvopathy requiring treatment
Clear my responses

How to participate?

Step 1 Connect with a study center
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar

Primary Contact

site

0/250

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider

Loading...

Browse trials for

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

user name

Added by • 

 • 

Private

Reply by • Private
Loading...

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.
Loading...

No annotations made yet

Add a private note
  • abc Select a piece of text from the left.
  • Add notes visible only to you.
  • Send it to people through a passcode protected link.
Add a private note